An analysis of the safety of Sevoflurane drugs: A disproportionality analysis based on Food and Drug Administration Adverse Event Reporting System

Sevoflurane is a volatile anesthetic that can tolerate inhalation induction and is widely used for inducing anesthesia due to its pleasant odor. As a drug that has been on the market for nearly 30 years, the vast majority of adverse reactions have been documented. This study aims to improve the adverse reactions related to Sevoflurane through the mining, organizing and analysis of Food and Drug Administration Adverse Event Reporting System database data. We collected, organized, and analyzed reports from the first quarter of 2004 to the fourth quarter of 2022. We performed disproportionality analysis algorithms, including reporting odds ratio, the proportional reporting ratio values, to quantify the signal values of different adverse events (AEs). A total of 1126 AEs and 27 system organ classes were identified by performing statistics analysis system software. By combining algorithm calculations, we create a forest map of the top 30 AEs of the reporting odds ratio signal. Based on the reviewing relevant literature, we found that the vast majority of AEs have been reported in relevant studies. However, there is currently no study revealing the correlation between atrial fibrillation and Sevoflurane, which means that atrial fibrillation may be an unreported AE of Sevoflurane. In the present study, we found that atrial fibrillation may be a new adverse reaction of Sevoflurane through the Food and Drug Administration Adverse Event Reporting System database, which can function as a novel guideline to guide us in the more standardized use of Sevoflurane in clinical practice.


Introduction
Sevoflurane was first discovered by Pos Terell and successfully synthesized by Regan in 1968. [1]However, it was not put into clinical use until phase III clinical trial from Japan in 1986, which was related to the potential AEs it may have. [2]evoflurane is a colorless, transparent, aromatic, and nonvolatile liquid with stable chemical properties.At commonly used clinical concentrations, it will not burn or explode when in contact with oxygen. [3]Due to its pleasant odor and nonirritating effect on trachea, Sevoflurane is permitted for inhalation induction in children and adults. [4]In inhalation anesthesia, 95% to 98% of Sevoflurane is excreted through the lungs, while the rest is excreted through the liver and kidney pathways. [5]Since its launch, there have been many reports of adverse events related to Sevoflurane, including neurological, respiratory, and circulatory systems.However, overall, Sevoflurane is considered a relatively safe and reliable drug. [6]his study aims to explore the unreported adverse reactions of Sevoflurane through the FDA adverse event reporting system (FAERS) database.
Sevoflurane mainly acts on the human nervous system, which can increase dose-dependent intracranial pressure and reduce cerebrovascular resistance. [7]However, there are also relevant studies reporting that Sevoflurane may damage the human nervous system.For instance, Jiang et al [8] found that elderly patients over 65 years old are at increased risk of developing Alzheimer disease after inhaling inhaled anesthetics such as Sevoflurane.Moreover, Constant et al [9] reported that Sevoflurane may be related to cortical epileptic electroencephalogram signs and usually has no clinical symptoms.Moreover, according to research conducted by Sun et al, [10] we found an increased incidence of emergence delirium in children receiving Sevoflurane induced anesthesia.Malignant hyperthermia is a hereditary disease, which is characterized by hypermetabolic reaction to strong volatile anesthetic gases, including Halothane, Sevoflurane, etc. [11] However, increasing evidence has demonstrated that Sevoflurane may induce hyperthermia malignant, postoperative restlessness, and agitation in children, which may be closely related to early pain. [12,13]Zhao et al [14] conducted a meta-analysis revealing that compared to propofol anesthesia, children who received Sevoflurane anesthesia had a higher risk of restlessness, postoperative nausea, vomiting, and postoperative pain.According to Kraus review, [15] we found a significant increase in the incidence of diabetes insipidus in critically ill patients receiving Sevoflurane.Therefore, the incidence of neurological related adverse events (AEs) significantly increases in patients undergoing inhalation of Sevoflurane induced anesthesia.
In addition, Sevoflurane may also lead to complications in other systems.For example, similar to other halogenated volatile anesthetics, Sevoflurane can lead to dose-dependent cardiovascular suppression, which may affect blood flow in different organ systems. [16]The Gonzalo Pascual team [17] believes that the incidence of severe acute hepatitis significantly increases after receiving Sevoflurane anesthesia.Additionally, Goa et al [18] proposed that similar to Halothane, Sevoflurane may cause emergency events such as cough, laryngospasm, agitation, and excitement, but Sevoflurane has a lower probability of causing arrhythmia than Halothane.Furthermore, Shutes et al [19] found an unusual complication of Sevoflurane in severe childhood cases, which can cause hypercapnia.Besides, Barrons et al [20] published a case report reporting on a 32 year old young woman who experienced rhabdomyolysis after receiving Sevoflurane.
In the present study, we obtained the AEs and clinical data of patients from the FAERS database, and then conducted disproportionality analysis to calculate the reporting odds ratios (RORs) values and corresponding 95% CIs of different system organ classes (SOCs) and PTs.Subsequently, we ranked the RORs values to obtain the AEs of Sevoflurane.Our research findings can help doctors better understand the risks associated with the use of Sevoflurane, thereby enabling more thorough communication with patients before surgery.

Data acquisition
This study is a retrospective study aimed at exploring the adverse reactions of Sevoflurane through the FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html).The AEs and clinical information of patients from over 100 countries were acquired from FAERS database.The FAERS database is a free and publicly available database that is updated quarterly and records adverse reactions from the first quarter of 2004 to the fourth quarter of 2022.Sevoflurane for inhalation was FDA certified and approved for sale in the United States in June 1995.Therefore, the AEs of Sevoflurane from the first quarter of 2004 to the fourth quarter of 2022 were included in our subsequent research (Fig. 1).

Detection of drug signals
The disproportionality analysis was conducted to evaluate the relationship between the AE signals and Sevoflurane by performing the ROR and proportional reporting ratio (PRR) algorithm. [24]The formula of ROR and PRR were listed as follows: Equation: a, number of reports containing both the target drug and target adverse drug reaction; b, number of reports containing other adverse drug reaction of the target drug; c, number of reports containing the target adverse drug reaction of other drugs; d, number of reports containing other drugs and other adverse drug reactions.

Signal analysis
Based on the AE signals, we explored the potential relationship among the AE signals, SOC and preferred term (PT).We recognized the clinical information of patients (e.g., survival outcomes, reporter, age, and reporting country), which was shown in Table 1.The forest map was generated to exhibit the RORs and 95% CI of AEs related to Sevoflurane.

Results
Data extraction obtained 1649 Sevoflurane AE reports, 817 women and 832 men.The survival outcomes, reporter, age, and reporting country of AE patients are shown in (Table 1).Men reported more ADEs, and the reported clinical outcomes of ADEs were more serious.We filtered 1126 AE signals related to Sevoflurane, 558 of which were identified as positive signals (Fig. 2).Regarding AE signals, we obtained 5 SOCs (injury, poisoning and procedural complications, general disorders and administration site conditions, respiratory, thoracic and mediastinal disorders, cardiac disorders, and nervous system disorders and psychiatric disorders), in which injury, poisoning and procedural complications exhibited the strongest signals (Table 2).Additionally, it is worth mentioning that according to time to onset of Sevoflurane-associated AEs in Figure 3, we found that the vast majority of AEs occurred within 30 days after receiving Sevoflurane anesthesia.The injury, poisoning, and complications included anesthetic complication neurological, unwanted awareness during anesthesia, mental status changes postoperative, anesthetic complication, delayed recovery from anesthesia, post-procedural complication, occupational exposure to product, and fetal exposure during pregnancy.General disorders and administration site conditions exhibited the second strongest signal strength, including hyperthermia malignant, hyperthermia, drug interaction, and chills.Respiratory, thoracic and mediastinal disorders showed the third strongest signal strength, including laryngospasm, hypercapnia, pulmonary alveolar hemorrhage, apnoea, bronchospasm, hypoxia, pulmonary edema, and respiratory failure.Cardiac disorders emerged as the fourth strongest signal strength, including ventricular fibrillation, torsade de pointes ventricular tachycardia, bradycardia, cardiac arrest, tachycardia, atrial fibrillation, and cardiorespiratory arrest.Nervous system disorders and psychiatric disorders revealed the fifth strongest signal strength, including delirium and seizure.

Discussion
According to the calculation of adverse reaction signals of Sevoflurane in the FAERS database, we found that most AEs have been reported.For instance, as stated in the introduction, the main AE of Sevoflurane is its neurotoxicity, which can also cause epilepsy, delirium, postoperative restlessness, and agitation.[27] Furthermore, as an inhaled anesthetic, Sevoflurane inevitably causes anesthesia complications (postoperative nausea, vomiting, postoperative pain), Delayed recovery from anesthesia, post-procedural complication, and occupational exposure to product.As for fetal exposure during pregnancy, increasing evidence have demonstrated that the fetal toxicity caused by exposure to Sevoflurane during pregnancy involves oxidative stress, neuroinflammation, and cognitive impairment. [10]s reported, Sevoflurane can cause hyperthermia malignant, hyperthermia, and drug interaction.According to relevant research, children receive Sevoflurane induced anesthesia are often more prone to hyperthermia malignant and hyperthermia, which is related to the damage of thermoregulation center. [28]dditionally, Sevoflurane can generate additive interactions with N(2)O and synergistic interactions with opioid drugs. [29]gure 3.Time to onset of sevoflurane-associated adverse events.The vast majority of AEs occurred within 30 days after receiving Sevoflurane anesthesia.AEs = adverse events.
As for the complications of the respiratory, thermal, and medical disorders system, they are consistent with the reported findings as well.For instance, after receiving Sevoflurane inhalation anesthesia, the child can cause laryngospasm and can be treated with intramuscular injection of succinylcholine. [30]urthermore, Brittany team has reported that Sevoflurane may cause hypercapnia in children. [19]Ahmed-Khan et al [31] reported that Sevoflurane could cause diffuse pulmonary alveolar hemorrhage.Therefore, if hemoptysis and hypoxemia occur after Sevoflurane induction, we should be alert to the possibility of alveolar hemorrhage.In addition, the recent literature have also reported that Sevoflurane can cause hypoxia, apnea, hypoxemia, bronchial obstruction, and pneumothorax. [32]According to a case report from Japan, we found that a 9-year-old Japanese boy developed bronchospasm and hypercapnia after Sevoflurane anesthesia. [33]Moreover, related literature have reported that Sevoflurane can cause pulmonary edema and airway bleeding in goats, and can also cause pulmonary edema in humans. [34,35]n addition, according to a retrospective study of 5864 cases conducted in Spain, we found that although Sevoflurane could have good anesthesia effects, it had also led to severe respiratory failure in several cases. [36]egarding cardiac disorders, we found that the vast majority of AEs were the same as reported.For example, under Sevoflurane anesthesia, it is more likely to cause ventricular fibrillation and torsade de pointe. [37,38]Besides, Sevoflurane can cause multiform ventricular tachycardia, which is believed to be caused by prolonging the Q-T interval. [39]Furthermore, related studies have also found that children experience significant rapid onset of bradycardia during Sevoflurane induced anesthesia. [40]urthermore, related cases have also been reported to experience sudden cardiac arrest after receiving Sevoflurane anesthesia. [41]owever, there are also several AEs have not been reported yet, which are also the AE need to be focused on.At present, there are no relevant research reports on the correlation between atrial fibrillation and Sevoflurane.However, based on our ROR values, we found that there is a certain possibility of inducing atrial fibrillation in patients receiving Sevoflurane anesthesia.Therefore, we do not recommend using Sevoflurane anesthesia for patients with arrhythmia.
We were the first to conduct a systematic analysis of adverse reactions of Sevoflurane drugs through the FAERS database.In addition, based on our results, we found that atrial fibrillation is also a common AE of Sevoflurane, but there are currently no relevant reports on the correlation between the 2.However, our research is still remain an analysis of public database, and the correlation between atrial fibrillation and Sevoflurane needs further clinical research to confirm.
In Summary, we downloaded and analyzed the results of the FAERS database, and obtained the most common adverse reactions of Sevoflurane, most of which are closely related to clinically discovered adverse reactions.In addition, we also found that Sevoflurane can cause a novel AE, namely atrial fibrillation, which provides a theoretical basis for guiding our clinical use of Sevoflurane.

Figure 1 .
Figure 1.Flowchart for the safety analysis of Sevoflurane.

Figure 2 .
Figure 2. Identification of the AE signals related to Sevoflurane.We filtered 1126 AE signals related to Sevoflurane, 558 of which were identified as positive signals (as shown in this figure).Regarding AE signals, we obtained 5 SOCs (injury, poisoning, and procedural complications, general disorders and administration site conditions, respiratory, thoracic and mediastinal disorders, cardiac disorders, and nervous system disorders and psychiatric disorders), in which injury, poisoning, and procedural complications exhibited the strongest signals.AE = adverse event, SOCs = system organ classes.

Table 1
The survival outcomes, reporter, age, and reporting country of AE patients.

Table
Signal strength of reports of Sevoflurane at the Top 30 PTs in FAERS database.